Modeling the Molecular Heterogeneity of Glioblastoma

Info

Trainee:

Robbie McNeil

Research Mentor:

Ryan Miller

Clinical Co-mentor:

Matt Ewend

Home Department

Pathology

Project Description

Glioblastoma (GBM) is the most common primary malignant brain tumor and has a median survival of 12 months. Current standard-of-care consists of external beam radiation (XRT) and DNA alkylating agents such as temozolomide (TMZ). However, human GBM (hGBM) are molecularly heterogeneous and consist of four expression profile-defined subtypes, each with distinct patterns of somatic/epigenetic alterations and responses to TMZ-XRT. Animal models that accurately recapitulate this molecular and phenotypic heterogeneity have yet to be developed. Thus, lack of animal models that mimic different molecular subtypes of hGBM represents a significant bottleneck, not only for the study of disease pathogenesis, but for pre-clinical drug testing as well. We propose to develop murine allograft models utilizing mature, terminally differentiated astrocytes (MA) harvested from genetically engineered mice (GEM) with conditional genetic lesions in pathways relevant to hGBM pathogenesis: RB, RTK, and TP53. Oncogenic events in the RTK pathway, including KRAS and NF1, are mutually exclusive. These findings suggest that they may be functionally equivalent for glioma initiation/progression. However, divergent signaling within and among the two major effector arms of RTK signaling, governed by the mitogen-activated protein kinase (MAPK) and phosphoinositol-3-kinase (PI3K) cascades, are likely to elicit distinct molecular GBM phenotypes and differential susceptibility to pharmacological inhibition. By examining different combinations of oncogenic alterations, we will develop models that faithfully recapitulate the histological and molecular heterogeneity of hGBM. Moreover, we will utilize these models for “co-clinical trials” (Chen, et al., Nature 2012) using standard-of-care therapy (TMZ-XRT) and BKM120, a PI3K inhibitor currently being investigated in clinical trials for hGBM. These models will provide a unique platform for examining the efficacy of novel drug combinations in preclinical GEM trials, the results of which may influence future clinical trial design for specific molecularly-defined subtypes of hGBM.